Traumatic brain injury (TBI) results in significant acute neurobehavioral deficits that, despite some spontaneous recovery persist at more chronic times. At least 5.3 million Americans - 2% of the U.S. population currently lives with disabilities resulting from TBI. However, beyond acute interventions there are currently no generally accepted medical treatments for reducing secondary neuropathology and promoting functional recovery after TBI. The central hypotheses of the proposed research are that: (1) limited functional recovery after TBI is due, at least in part, to inadequate axonal sprouting, (2) limited sprouting is a result of an increase in growth-inhibitory molecules (growth-IMs), (3) treatment to reduce growth-IMs will improve functional outcome, and (4) combined treatments to reduce growth-IMS and to activate cellular growth will further enhance sprouting and functional outcome. We base this hypothesis on observations after controlled-cortical impact (CCI) injury, a clinically relevent model of TBI that: 1) a persistent behavioral deficit occurs, despite functional imaging data showing activation in novel ipsi-lesional regions, 2) spontaneous axon sprouting occurs only in regions of reduced growth-inhibitory chondroitin sulphate proteoglycans (CSPGs), 3) pharmacological reduction of CSPGs increases perilesional sprouting and 4) the same treatment-induced sprouting is the anatomical substrate for enhanced functional outcome after spinal cord injury which also prolongs the critical period for plasticity in dark-reared cats. Based on these observations the focus of this proposal is on the growth-inhibitory activity of the CSPGs and their contribution to failed axon plasticity after TBI. The specific aims are to: (i) Determine the relationship between CSPG expression and spontaneous axon sprouting after CCI injury. We will examine whether spontaneous axon sprouting occurs only in regions where CSPG expression is low and where perineuronal net organization of CSPGs is reduced, (ii) Determine whether attenuating CSPG protein expression enhances subsequent axonal sprouting. We will use chondroitinase ABC to reduce ipsi-lesional CSPG proteins to enhance and sustain axonal sprouting, (iii) Determine whether axon sprouting is regionally and temporally specific to novel regions of fore-limb evoked functional activation after injury. We will assess whether axonal sprouting provides the anatomical substrate for functional recovery in the same animal, (iv) Determine if attenuating CSPG expression improves functional and neurobehavioural outcome. We will use functional microPET imaging and behavioral tests of fore-limb function to determine if enhancing sprouting improves outcome, (v) Determine if activating cellular growth status by BDNF infusion combined with attenuation of CSPG expression results in further increases in sprouting and improved behavioral outcome.